Proteomic analysis of non-muscle invasive and muscle invasive bladder cancer highlights distinct subgroups with metabolic, matrisomal, and immune hallmarks and emphasizes importance of the stromal compartment

We present the proteomic profiling of 79 bladder cancers, including treatment-naïve non-muscle-invasive bladder cancer (NMIBC, n = 17), muscle-invasive bladder cancer (MIBC, n = 51), and neoadjuvant-treated MIBC (n = 11). Proteins were extracted from formalin-fixed, paraffin-embedded samples and ana...

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Autores: Dinh, Thien-Ly Julia, Espadas, Guadalupe, Sabidó Aguadé, Eduard, 1981-, Schilling, Oliver
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2025
País:España
Institución:Universitat Pompeu Fabra
Repositorio:Repositorio Digital de la UPF
OAI Identifier:oai:repositori.upf.edu:10230/69401
Acceso en línea:http://hdl.handle.net/10230/69401
http://dx.doi.org/10.1002/path.6367
Access Level:acceso abierto
Palabra clave:Bladder cancer
Proteomics
Tumor microenvironment
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spelling Proteomic analysis of non-muscle invasive and muscle invasive bladder cancer highlights distinct subgroups with metabolic, matrisomal, and immune hallmarks and emphasizes importance of the stromal compartmentDinh, Thien-Ly JuliaEspadas, GuadalupeSabidó Aguadé, Eduard, 1981-Schilling, OliverBladder cancerProteomicsTumor microenvironmentWe present the proteomic profiling of 79 bladder cancers, including treatment-naïve non-muscle-invasive bladder cancer (NMIBC, n = 17), muscle-invasive bladder cancer (MIBC, n = 51), and neoadjuvant-treated MIBC (n = 11). Proteins were extracted from formalin-fixed, paraffin-embedded samples and analyzed using data-independent acquisition, yielding >8,000 quantified proteins. MIBC, compared to NMIBC, shows an extracellular matrix (ECM) and immune response signature as well as alteration of the metabolic proteome together with concomitant depletion of proteins involved in cell-cell adhesion and lipid metabolism. Neoadjuvant treatment did not consistently impact the proteome of the residual tumor mass. NMIBC presents two proteomic subgroups that correlate with histological grade and feature signatures of cell adhesion or lipid/DNA metabolism. Treatment-naïve MIBC presents three proteomic subgroups with resemblance to the basal-squamous, stroma-rich, or luminal subtypes and signatures of metabolism, immune functionality, or ECM. The metabolic subgroup presents an immune-depleted microenvironment, whereas the ECM and immune subgroups are enriched for markers of M2-like tumor-associated macrophages and dendritic cells. Markers for natural killer cells are exclusive for the ECM subgroup, and markers for cytotoxic T cells are a hallmark of the immune subgroup. Endogenous proteolysis is increased in MIBC alongside upregulation of matrix metalloproteases, including MMP-14. Genomic panel sequencing yielded the prototypical profile of prevalent FGRF3 alterations in NMIBC and TP53 alterations in MIBC. Tumor-stroma interactions of MIBC were investigated by proteomic analysis of patient-derived xenografts, highlighting specific tumor and stroma contributions to the matrisome and tumor-induced stromal proteome phenotypes. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.Wiley202520252025info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttp://hdl.handle.net/10230/69401http://dx.doi.org/10.1002/path.6367reponame:Repositorio Digital de la UPFinstname:Universitat Pompeu FabraInglésJ Pathol. 2025 Jan;265(1):41-56© 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.http://creativecommons.org/licenses/by-nc/4.0/info:eu-repo/semantics/openAccessoai:repositori.upf.edu:10230/694012026-06-12T07:21:37Z
dc.title.none.fl_str_mv Proteomic analysis of non-muscle invasive and muscle invasive bladder cancer highlights distinct subgroups with metabolic, matrisomal, and immune hallmarks and emphasizes importance of the stromal compartment
title Proteomic analysis of non-muscle invasive and muscle invasive bladder cancer highlights distinct subgroups with metabolic, matrisomal, and immune hallmarks and emphasizes importance of the stromal compartment
spellingShingle Proteomic analysis of non-muscle invasive and muscle invasive bladder cancer highlights distinct subgroups with metabolic, matrisomal, and immune hallmarks and emphasizes importance of the stromal compartment
Dinh, Thien-Ly Julia
Bladder cancer
Proteomics
Tumor microenvironment
title_short Proteomic analysis of non-muscle invasive and muscle invasive bladder cancer highlights distinct subgroups with metabolic, matrisomal, and immune hallmarks and emphasizes importance of the stromal compartment
title_full Proteomic analysis of non-muscle invasive and muscle invasive bladder cancer highlights distinct subgroups with metabolic, matrisomal, and immune hallmarks and emphasizes importance of the stromal compartment
title_fullStr Proteomic analysis of non-muscle invasive and muscle invasive bladder cancer highlights distinct subgroups with metabolic, matrisomal, and immune hallmarks and emphasizes importance of the stromal compartment
title_full_unstemmed Proteomic analysis of non-muscle invasive and muscle invasive bladder cancer highlights distinct subgroups with metabolic, matrisomal, and immune hallmarks and emphasizes importance of the stromal compartment
title_sort Proteomic analysis of non-muscle invasive and muscle invasive bladder cancer highlights distinct subgroups with metabolic, matrisomal, and immune hallmarks and emphasizes importance of the stromal compartment
dc.creator.none.fl_str_mv Dinh, Thien-Ly Julia
Espadas, Guadalupe
Sabidó Aguadé, Eduard, 1981-
Schilling, Oliver
author Dinh, Thien-Ly Julia
author_facet Dinh, Thien-Ly Julia
Espadas, Guadalupe
Sabidó Aguadé, Eduard, 1981-
Schilling, Oliver
author_role author
author2 Espadas, Guadalupe
Sabidó Aguadé, Eduard, 1981-
Schilling, Oliver
author2_role author
author
author
dc.subject.none.fl_str_mv Bladder cancer
Proteomics
Tumor microenvironment
topic Bladder cancer
Proteomics
Tumor microenvironment
description We present the proteomic profiling of 79 bladder cancers, including treatment-naïve non-muscle-invasive bladder cancer (NMIBC, n = 17), muscle-invasive bladder cancer (MIBC, n = 51), and neoadjuvant-treated MIBC (n = 11). Proteins were extracted from formalin-fixed, paraffin-embedded samples and analyzed using data-independent acquisition, yielding >8,000 quantified proteins. MIBC, compared to NMIBC, shows an extracellular matrix (ECM) and immune response signature as well as alteration of the metabolic proteome together with concomitant depletion of proteins involved in cell-cell adhesion and lipid metabolism. Neoadjuvant treatment did not consistently impact the proteome of the residual tumor mass. NMIBC presents two proteomic subgroups that correlate with histological grade and feature signatures of cell adhesion or lipid/DNA metabolism. Treatment-naïve MIBC presents three proteomic subgroups with resemblance to the basal-squamous, stroma-rich, or luminal subtypes and signatures of metabolism, immune functionality, or ECM. The metabolic subgroup presents an immune-depleted microenvironment, whereas the ECM and immune subgroups are enriched for markers of M2-like tumor-associated macrophages and dendritic cells. Markers for natural killer cells are exclusive for the ECM subgroup, and markers for cytotoxic T cells are a hallmark of the immune subgroup. Endogenous proteolysis is increased in MIBC alongside upregulation of matrix metalloproteases, including MMP-14. Genomic panel sequencing yielded the prototypical profile of prevalent FGRF3 alterations in NMIBC and TP53 alterations in MIBC. Tumor-stroma interactions of MIBC were investigated by proteomic analysis of patient-derived xenografts, highlighting specific tumor and stroma contributions to the matrisome and tumor-induced stromal proteome phenotypes. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
publishDate 2025
dc.date.none.fl_str_mv 2025
2025
2025
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10230/69401
http://dx.doi.org/10.1002/path.6367
url http://hdl.handle.net/10230/69401
http://dx.doi.org/10.1002/path.6367
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv J Pathol. 2025 Jan;265(1):41-56
dc.rights.none.fl_str_mv http://creativecommons.org/licenses/by-nc/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by-nc/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Wiley
publisher.none.fl_str_mv Wiley
dc.source.none.fl_str_mv reponame:Repositorio Digital de la UPF
instname:Universitat Pompeu Fabra
instname_str Universitat Pompeu Fabra
reponame_str Repositorio Digital de la UPF
collection Repositorio Digital de la UPF
repository.name.fl_str_mv
repository.mail.fl_str_mv
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